Genetically Modified Animals: From the Lab, To the Lab

Genetically Modified Animals (GMAs) are used in the majority of labs conducting biomedical research worldwide. According to the European Health Safety Authority, GMAs are animals that have undergone modifications in their genetic material, such as additions, deletions or alterations in the sequence of their DNA (European Food Safety Authority, 2017) This process has gained significant attention due to its potential to enhance scientific research and increase the understanding of human disease. However, due to this high level of intervention to the animal’s genome, ethical considerations are arising. This article goes through the techniques to create GMAs, their applications and ethical issues that concern the scientific community and the rest of the society as well.

Lab Techniques for Creating GMAs

There are several ways to create GMAs in the lab. Most of them involve gene editing or introduction of new genetic material into the animal’s cells. As seen in gene therapy techniques, genetic modifications can be introduced into the animal’s cells with the use of a vector, such as a virus or a phage. The transgenic vector carries the desired gene, along with a promoter and a termination sequence, giving the opportunity to the cellular machinery to transcribe and translate the gene (Whitelaw et al., 2004). Another way to introduce a modification into the animal’s cells is directly by microinjection. The DNA in solution is injected into the nucleus either of a somatic cell or of a fertilized oocyte. These two techniques are recognized under the term “transgenesis” and are mostly used for gene addition. The most challenging, but at the same time most common genetic modifications to introduce are gene knockouts. In the past, the only way to study gene function, was to find humans or animals, suffering from hereditary genetic disease and probably missing an allele of a specific gene. This process was time-consuming and often inefficient. Nowadays, there are several lab techniques to knockout a gene. The most common one is targeted integration. In this case, a piece of DNA is inserted into specific parts of the sequence of the desired gene, deactivating it. The animal’s organism has a natural process that allows this technique (Lanigan, Kopera, & Saunders, 2020). This process is called homologous recombination (HR). This is a biological process that occurs during DNA repair, genetic recombination and the formation of gametes. It involves the exchange of genetic material between two similar or identical DNA molecules, typically occurring between homologous chromosomes (Wright, Shah, & Heyer, 2018). Finally, introduction of CRISPR and other revolutionary gene editing techniques, such as Cre-Lox recombination have greatly facilitated genetic modifications in animals, allowing precise genetic modifications and avoiding, as much as possible, off-target events. These modern techniques also take advantage of the process of homologous recombination. After the desired genetic information is introduced into the animal, cellular machinery is doing the actual editing of the genome (Lino, Harper, Carney, & Timlin, 2018).

Figure 1: Gene Editing (Rees, 2020)

Applications of GMAs in the lab and in the society

As mentioned earlier, GMAs are possibly used in the majority of biomedical labs around the world. The main reason to create GMAs is to understand the function of genes in the context of a complex organism, model human diseases and test possible therapies. Common examples used in GMAs are the worms Caenorhabditis elegans (C. elegans), zebrafish, fruit flies and mice. the mouse genome, for example, has an 80-90% similarity to the human genome. Mouse models are excellent tools to explore nervous, cardiovascular, skeletal, immune and other complex physiological systems (Zhou, Grinchuk, & Tomarev, 2008). In addition, mice naturally develop diseases such as cancer, diabetes and atherosclerosis, diseases that are widely studied by scientists. Finally, they can reproduce easy and quickly. Until today labs are able to create transgenic mice, knockout mice and knock-in mice. Another interesting application of GMAs is “pharming”. This term is a combination of the words farming and pharmaceutical. Gene pharming includes the production of recombinant proteins from live animals. For example, introducing a human hormone in a sheep, via recombinant DNA technology, the milk that the sheep produces will contain the human hormone. Such animals can also be used in agriculture to enhance animal productivity and disease resistance (Kind & Schnieke, 2008). Lastly, it is worth mentioning here that Dolly the Sheep was not a genetically modified animal. She was actually cloned using a non-modified cell.

Figure 2: Dolly the Sheep (middle) (Weintraub, 2016)

Practical and Ethical Concerns

The release of GMAs into the environment raises concerns about potential ecological impacts, such as the spread of modified genes to wild populations as well as unintended ecological disruptions. Moreover, unintended consequences such as off-target effects in gene editing or unexpected physiological changes, need to be carefully studied and monitored to ensure the safety and well-being of both GMAs and their ecosystems. Risk assessment strategies and robust biosafety protocols are essential to minimize such risks.

Ethical discussions around GMAs concern mainly the respect towards animals and their intrinsic value. Consideration must be given to their well-being, including their physical and psychological needs as well as their ability to express their natural behaviors (Sunstein & Nussbaum, 2005). This is why regulatory and ethical comities have set quite strict rules about the use of animals in lab research, ensuring that animals will be treated in the most respectful and least painful way (Niemann & Kues, 2007). More ethical and less intrusive lab techniques are currently arising, giving the opportunity to minimize the use of animal models. Furthermore, critics question the moral implications of “playing God” and tampering with the fundamental building blocks of life. Induced Pluripotent Stem Cells (iPSCs) and organoids can model human organs and disease, allowing scientists to eliminate experiments on animal models (Aboul-Soud, Alzahrani, & Mahmoud, 2021).

Conclusion

Genetically modified animals offer significant potential for improving lab techniques, advancing medical research, and discovering treatments for human disease. However, their development and use raise important ethical considerations and require careful regulation and oversight. By addressing biosafety concern, ensuring animal welfare, and engaging in transparent ethical discussions, we can harness the benefits of GMAs while upholding responsible and ethical practices in their application.

Bibliographical References

Aboul-Soud, M. A., Alzahrani, A. J., & Mahmoud, A. (2021). Induced pluripotent stem cells (ipscs)—roles in regenerative therapies, disease modelling and drug screening. Cells, 10(9), 2319. doi:10.3390/cells10092319

https://doi.org/10.1167/iovs.07-1339

European Food Safety Authority (EFSA). Genetically modified animals. Retrieved from:

https://www.efsa.europa.eu/en/topics/topic/genetically-modified-animals

Kind, A., & Schnieke, A. (2008). Animal pharming, two decades on. Transgenic Research, 17(6), 1025–1033. doi:10.1007/s11248-008-9206-3

https://doi.org/10.1007/s00429-009-0230-8

Lanigan, T. M., Kopera, H. C., & Saunders, T. L. (2020). Principles of genetic engineering. Genes, 11(3), 291. doi:10.3390/genes11030291

https://doi.org/10.3390/genes11030291

Lino, C. A., Harper, J. C., Carney, J. P., & Timlin, J. A. (2018). DELIVERING CRISPR: A review of the challenges and approaches. Drug Delivery, 25(1), 1234–1257. doi:10.1080/10717544.2018.1474964

https://doi.org/10.1080/10717544.2018.1474964

Niemann, H., & Kues, W. A. (2007). Transgenic Farm Animals: An update. Reproduction, Fertility and Development, 19(6), 762. doi:10.1071/rd07040

https://doi.org/10.1071/RD07040

Sunstein, C. R., & Nussbaum, M. C. (2005). Animal rights: current debates and New Directions. Oxford Academic. doi:10.1093/acprof:oso/9780195305104.001.0001

https://doi.org/10.1093/acprof:oso/9780195305104.001.0001

Whitelaw, C. B. A., Radcliffe, P. A., Ritchie, W. A., Carlisle, A., Ellard, F. M., Pena, R. N., … Mitrophanous, K. A. (2004). Efficient generation of transgenic pigs using equine infectious anaemia virus (EIAV) derived vector. FEBS Letters, 571(1–3), 233–236. doi:10.1016/j.febslet.2004.06.076

https://doi.org/10.1016/j.febslet.2004.06.076

Wright, W. D., Shah, S. S., & Heyer, W.-D. (2018). Homologous recombination and the repair of DNA double-strand breaks. Journal of Biological Chemistry, 293(27), 10524–10535. doi:10.1074/jbc.tm118.000372

https://doi.org/10.1074/jbc.TM118.000372

Zhou, Y., Grinchuk, O., & Tomarev, S. I. (2008). Transgenic mice expressing the tyr437his mutant of human Myocilin protein develop glaucoma. Investigative Opthalmology & Visual Science, 49(5), 1932. doi:10.1167/iovs.07-1339

https://doi.org/10.1167/iovs.07-1339

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